Academic literature on the topic 'Terapia specifica'

I modelli di terapia familiare spesso non riflettono le realtŕ e i desideri di molte coppie gay e lesbiche. Spetta ai terapeuti che lavorano con questa popolazione decidere se applicare questi modelli cosě come sono, rifiutarli o tentare di modificarli nel corso del lavoro con i loro clienti. Questo articolo, utilizzando risultati di ricerca e casi clinici che descrivono i confini intergenerazionali delle coppie gay e lesbiche e le relazioni non monogame degli omosessuali, vuole illustrare come i terapeuti possano adattare i modelli di terapia familiare per soddisfare i bisogni e le preferenze della specifica popolazione costituita dai loro clienti

Nella encefalite erpetica tipo I (HSV-1) in età pediatrica il contributo delle indagini diagnostiche neuroradiologiche quali la TC e la RM, i progressi delle conoscenze cliniche e virologiche, consentono di valutare precocemente le lesioni cerebrali nella fase acuta della malattia, permettendo rapidamente l'inizio di una terapia antivirale specifica e limitando pertanto le indicazioni alla biopsia cerebrale, ancor oggi unico mezzo capace di porre una diagnosi certa.

Il trattamento delle malattie mieloproliferative richiede sempre più frequentemente il coinvolgimento della figura del nefrologo nella gestione terapeutica. Il nefrologo è chiamato a mettere in atto una serie di provvedimenti terapeutici che mirino a correggere fattori precipitanti la funzionalità renale. Mostreremo un caso emblematico di gestione ematologica e nefrologica di un caso di mieloma multiplo di tipo micromolecolare con severa compromissione renale trattato con successo con associazione di Velcade e desametasone in 8 cicli in un periodo di 6 mesi. In questo periodo il paziente è stato supportato con terapia medica e infusionale per mantenere un'adeguata idratazione, una costante alcalinizzazione delle urine, buoni livelli di albuminemia, calcemia e uricemia senza ricorrere a trattamento dialitico sostitutivo. Non viene mai sospeso il trattamento chemioterapico e gli effetti tossici più importanti vengono monitorati e trattati con terapia specifica senza mai ridurre il dosaggio del chemioterapico. Si ottiene un progressivo recupero della funzione renale oltre a una remissione della malattia di base.

Il lavoro si propone di portare l'attenzione sulle connessioni fra fenomeni di regressione e fenomeni di sublimazione all'interno dell'esperienza clinica della psicoterapia psicoanalitica. Attraverso varie teorizzazioni si riflette sulla terapia analitica intesa come un processo che si muove fra luoghi della mente caratterizzati da indistinzione, linguaggio primario, memorie sensoriali e aree più differenziate, dove domina la rappresentazione, il tempo lineare, la narra-zione, un tipo di pensiero secondario. Si riflette su come questo andamento oscillatorio non sia un limite o un sintomo, né della persona né del suo percorso terapeutico, ma possa esserne l'aspetto vitale e creati-vo, che da luogo ad autentiche e soggettive trasformazioni e creazioni. La terapia stessa, intesa in questo modo, viene rapportata ad un'esperienza estetica dove il bello e il vero sono intesi innanzitutto come qualcosa di profondamente originale e soggettivo, proveniente dal nucleo originario della mente specifica nell'incontro con il terapeuta. La stessa relazione analitica diventa una relazione che può e deve attraversare momenti di fusionalità sana.

La crisi della coppia: tre ipotesi teorico-cliniche alternative, di Alberto Eiguer. L'autore studia in questo testo tre ipotesi che privilegiano l'idea di novitŕ: 1) la psiche della coppia non č il prodotto esclusivo della psiche individuale dei partner, bensě la creazione di un processo psichico specifico; 2) la crisi della coppia č animata da funzionamenti originali perché non si potrebbe spiegarla con la sua strutturazione abituale; 3) č specifica rispetto alle altre crisi: č l'espressione di conflitti aperti aspri e manifesti che mettono in gioco la differenza tra i generi. Pertanto, l'autore ricorda i concetti teorici sulla teorica della crisi e le manifestazioni di quest'ultima quando colpisce la coppia. Nonostante corroda profondamente la coppia, questa puň uscirne rafforzata dalla prova. La crisi svela le faglie del riconoscimento dell'altro nella sua alteritŕ. L'esempio di terapia psicanalitica di coppia permette di illustrare queste idee.

Il Lupus Eritematoso Sistemico (LES) è una connettivite autoimmune sistemica che coinvolge più frequentemente la cute e il sistema muscolo-scheletrico e articolare. Quadri di LES “grave” all'esordio possono presentarsi con manifestazioni cliniche aspecifiche ed evolvere rapidamente verso l'insufficienza multiorgano. Abbiamo riportato il caso di un paziente affetto da LES sistemico, non precedentemente diagnosticato, esordito con sintomatologia gastrointestinale e iperpiressia. I dati di laboratorio all'ingresso segnalavano insufficienza renale acuta, proteinuria ed emoglobinuria. L'evoluzione rapida e infausta verso l'insufficienza multiorgano e l'exitus (venti giorni) sottolineano l'importanza di riconoscere tempestivamente segni clinici e di laboratorio suggestivi per LES “grave”, in modo da avviare il più precocemente possibile una terapia immunosoppressiva specifica.

L'aferesi ha conosciuto nel tempo, per evoluzione dei materiali d'uso, diversificazione delle tecniche e possibilità di impiego clinico, un progresso tale da rappresentare un presidio terapeutico complesso che richiede specifiche conoscenze e competenze. In Europa, questa attività clinica è stata gestita in maniera poco attenta, tanto che, a oggi, non si riconoscono specifici ambiti di impiego né settori di utenza. Per tale motivo, nel 1993, si è costituito, in seno alla Società Italiana di Nefrologia, il Grappo di Studio dell'aferesi terapeutica. Infatti, in assenza di una specifica o univoca indicazione terapeutica, si rende necessario l'approccio multidisciplinare, che dovrà approdare alla redazione di Linee Guida condivise e a idonei marker di appropriatezza e di efficacia della terapia. Il consenso informato, espressione della volontà del cittadino malato che autorizza il medico a compiere uno specifico trattamento medico-chirurgico, acquisisce un ruolo fondamentale anche nell'ambito dell'aferesi terapeutica. Il medico non ha il “diritto di curare”, ma solo la “potestà” e la “facoltà” di curare su richiesta del paziente, al di fuori dei casi di emergenza. Pertanto, il consenso non è solamente un obbligo deontologico-contrattuale ma l'atto che legittima il trattamento per ogni singolo paziente. Quindi, suggeriamo un percorso standard per l'acquisizione del consenso nell'ambito dell'aferesi.

Tra i pazienti con diagnosi iniziale di cardiomiopatia ipertrofica afferiti a Centri di Riferimento per le Cardiomiopatie, l’AC è la malattia non riconosciuta più comune con una prevalenza complessiva del 9%, e che aumenta con l'età (dall'1% nella fascia di età tra i 40-49 anni al 26% sopra gli 80 anni). Nella popolazione generale ≥55 anni più del 7% ha almeno un reperto ecocardiografico suggestivo di AC e l’ispessimento del setto interatriale è quello più frequente. I pazienti con elevato sospetto di AC (≥3 reperti) rappresentano l’1% della popolazione generale e il 4,9% di quelli con cuore non dilatato, ipertrofico e con FE normale.
Among patients with initial diagnosis of HCM, cardiac amiloidosis has a prevalence of 9% and it increases with age. In the general population > 55 yo more than 7% has echocardiographic suspicion of the disease and echocardiography has an important role in the early diagnosis of the disease

Introduzione. L'infezione perinatale da HIV-1 è acquisita quando il sistema immunitario del bambino è in fase di sviluppo ed è caratterizzata da un'elevata e non controllata replicazione virale. La terapia antiretrovirale altamente efficace (HAART), che genericamente prevede l'utilizzo di inibitori della proteasi e della trascrittasi inversa, riduce efficientemente la carica virale di HIV-1 sotto livelli non rilevabili e aumenta il numero di cellule T CD4+ circolanti nei bambini come negli adulti. Al fine di incrementare le scarse informazioni sul trattamento precoce con HAART e sull'immunoricostituzione in bambini HIV-1-infetti, è stata analizzata la dinamica virale e la risposta immunitaria in bambini trattati precocemente con HAART e l'immunoricostituzione in bambini HIV-1-infetti che hanno mostrato una risposta discordante alla terapia. Metodi. Coorte in HAART precoce: sono stati studiati 6 neonati HIV-1-infetti che hanno iniziato HAART entro i 3 mesi di età. HIV-1 RNA plasmatico, HIV-1 DNA cellula-associato, HIV-1 mRNA unspliced e multiply spliced e anticorpi anti-HIV-1 sono stati analizzati in campioni sequenziali di sangue periferico. La risposta immunitaria cellulare HIV-1-specifica è stata misurata mediante saggio EliSpot. Coorte discordante: le sottopopolazioni cellulari T CD4+ e CD8+ sono state studiate al baseline e dopo circa 2 anni di HAART in 14 bambini HIV-1-infetti che hanno mostrato una soppressione della viremia plasmatica (rispondenti virologici, VR) e in 16 bambini non rispondenti virologici alla terapia (VNR). Risultati. Coorte in HAART precoce. In tutti i bambini è stata osservata una riduzione della viremia plasmatica. In 4 bambini è stato rilevato l’HIV-1 DNA; di questi 2 erano anche positivi per l’HIV-1 mRNA. Solo 2 bambini hanno prodotto propri anticorpi anti-HIV-1 mentre gli altri, dopo la perdita degli anticorpi materni, sono rimasti persistentemente sieronegativi. In nessun paziente è stata osservata una risposta immunitaria cellulare HIV-1-specifica. L’interruzione di terapia è stata effettuata in un paziente HIV-1-sieropositivo ed in uno sieronegativo. L’aumento della viremia plasmatica nel bambino sieronegativo è stato più rapido ed elevato rispetto a quello osservato nel paziente sieropositivo. Coorte discordate. Durante HAART è stato riscontrato un aumento delle cellule T CD4+ sia nei bambini VR sia nei VNR; tale incremento era più elevato nel primo gruppo rispetto a quello rilevato nel secondo. Tutte le sottopopolazioni cellulari T CD4+ (naive, central memory, effector/memory e CD38+) sono aumentate significativamente nei bambini VR mentre nei VNR l’incremento significativo avveniva solo nelle cellule naive. In entrambe i gruppi si è osservato un aumento nelle cellule T CD8+ naive e nella forma epitomale di riarrangiamento del recettore delle cellule T (TREC), un indicatore della funzionalità timica. Le cellule T CD8+CD38+ attivate sono diminuite nei bambini VR mentre sono rimaste elevate nei VNR. I livelli plasmatici di lipopolisaccaride (LPS), un indicatore della translocazione microbica, erano aumentati nei pazienti VNR. Conclusioni. La somministrazione precoce di HAART nel neonato modifica il naturale corso dell’infezione da HIV-1. Tale regime, sebbene controlli la replicazione virale, riduce la viremia plasmatica sotto i livelli soglia necessari ad induce una risposta immunitaria HIV-1-specifica e non previene l’istaurazione di una latenza virale che impedisce l’eradicazione dell’infezione. Un prolungato trattamento con HAART nei bambini HIV-1-infetti permette, inoltre, un aumento delle cellule T naive che è indipendentemente dalla risposta virologica alla terapia. Una viremia persistente, comunque, impedisce l’espansione delle cellule T CD4+ memory suscettibili all’infezione virale e, insieme alla translocazione microbica, contribuisce a mantenere elevati i livelli di immuno-attivazione.
Background. Perinatal HIV-1 infection is acquired in the milieu of a developing immune system, leading to high levels of uncontrolled viral replication. Highly active antiretroviral therapy (HAART), which is usually a combination of protease and reverse transcriptase inhibitors, efficiently reduces HIV-1 load to undetectable levels and increases the number of circulating CD4 T cells in children as well as adults. To add to the scarce information available on early HAART treatment and immune reconstitution in HIV-1-infected children, we investigated the viral dynamics and the immunological response in early HAART treated-children and the immune reconstitution in HIV-1-infected children with discordant response to therapy. Methods. Early HAART cohort: 6 HIV-1-infected infants who started HAART within 3 months of age were studied. Plasma HIV-1 RNA, cell-associated HIV-1 DNA, unspliced and multiply spliced HIV-1 mRNAs, HIV-1 antibodies were assessed in sequential peripheral blood samples. HIV-1 cellular immune response was measured by EliSpot assay. Discordant cohort: CD4+ and CD8+ T cell subsets in 14 HIV-1-infected children with suppression of HIV-1 plasma viraemia (virological responders, VR) and in 16 virological non responders (VNR) to therapy were studied at baseline and after approximately 2 years of HAART. Results. Early HAART cohort. All children showed a decline in plasma viraemia to undetectable levels. HIV-1 DNA persisted in 4 children, but only 2 of these had detectable HIV-1 mRNA. All viral parameters remained persistently negative in 2 children. Only 2 children produced HIV-1 antibodies, while the others, after having lost maternal antibodies, remained seronegative. No HIV-1 cellular immune response was observed in any child. Therapy interruption was performed in 2 children: one HIV-1-seropositive and one HIV-1-seronegative with persistently undetectable levels of all viral parameters. Rebound of HIV-1 plasma viraemia in the seronegative child was more rapid and higher than that observed in the seropositive child. Discordant cohort. During therapy, CD4+ T cells increased in both groups, but were higher in the VR than in the VNR group. All CD4+ T cell subsets (naive, central memory, effector/memory and CD38+) increased significantly in VR children, while there was a significant increase only in naive cells in VNR children. Naive CD8+ T cells and T cell receptor rearrangement excision circles (TREC), an indicator of thymic output, increased in both VR and VNR children. Activated CD8+CD38+ T cells decreased in VR but remained high in VNR children. Levels of circulating lipopolysaccharide (LPS), an indicator of microbial translocation, further increased in VNR children. Conclusions. Early ART treatment in infants modifies the natural course of infection by controlling HIV-1 replication and reducing viral load to below the threshold levels required for onset of HIV-1 immune response, but does not prevent the establishment of a reservoir of latently infected cells that precludes virus eradication. Moreover, a long-term HAART treatment induced an increase in naive T cells in all HIV-1-infected children, regardless of their virological response. However, the persistence of viraemia resulted in an impaired expansion of memory CD4+ T cells susceptible to HIV-1 infection, and together with the microbial translocation sustained the persistence of a high level of immune activation.

Hepatitis B virus (HBV) recurrence after orthotopic liver transplantation (OLT) is associated with poor graft and patient survival. Treatment with HBV-specific immunoglobulins (HBIG) in combination with nucleos(t)ide analogs is effective in preventing HBV reinfection of the graft and improving OLT outcome. However, the combined immunoprophylaxis has several limitations, mainly the high cost and the lack of standard schedules about duration. So far, the identification of markers able to predict the reinfection risk is needed. Although the HBV-specific immune response is believed to play an essential role in disease outcome, HBV-specific cellular immunity in viral containment in OLT recipients is unclear. To test whether or not OLT recipients maintain robust HBV-specific cellular immunity, the cellular immune response against viral nucleocapsid and envelope-protein of HBV was assessed in 15 OLT recipients and 27 individuals with chronic and 24 subjects with self-limited HBV infection, respectively. The data demonstrate that OLT recipients mounted fewer but stronger clusters of differentiation (CD)8 T cell responses than subjects with self-limited HBV infection and showed a preferential targeting of the nucleocapsid antigen. This focused response pattern was similar to responses seen in chronically infected subjects with undetectable viremia, but significantly different from patients who presented with elevated HBV viremia and who mounted mainly immune responses against the envelope protein. In conclusion, virus-specific CD4 T cell–mediated responses were only detected in subjects with self-limited HBV infection. Thus, the profile of the cellular immunity against HBV was in immune suppressed patients similar to subjects with chronic HBV infection with suppressed HBV-DNA.

Hepatitis B virus (HBV) recurrence after orthotopic liver transplantation (OLT) is associated with poor graft and patient survival. Treatment with HBV-specific immunoglobulins (HBIG) in combination with nucleos(t)ide analogs is effective in preventing HBV reinfection of the graft and improving OLT outcome. However, the combined immunoprophylaxis has several limitations, mainly the high cost and the lack of standard schedules about duration. So far, the identification of markers able to predict the reinfection risk is needed. Although the HBV-specific immune response is believed to play an essential role in disease outcome, HBV-specific cellular immunity in viral containment in OLT recipients is unclear. To test whether or not OLT recipients maintain robust HBV-specific cellular immunity, the cellular immune response against viral nucleocapsid and envelope-protein of HBV was assessed in 15 OLT recipients and 27 individuals with chronic and 24 subjects with self-limited HBV infection, respectively. The data demonstrate that OLT recipients mounted fewer but stronger clusters of differentiation (CD)8 T cell responses than subjects with self-limited HBV infection and showed a preferential targeting of the nucleocapsid antigen. This focused response pattern was similar to responses seen in chronically infected subjects with undetectable viremia, but significantly different from patients who presented with elevated HBV viremia and who mounted mainly immune responses against the envelope protein. In conclusion, virus-specific CD4 T cell–mediated responses were only detected in subjects with self-limited HBV infection. Thus, the profile of the cellular immunity against HBV was in immune suppressed patients similar to subjects with chronic HBV infection with suppressed HBV-DNA.

Le infezioni del tratto urinario (UTIs) sono fra le più frequenti infezioni umane. Escherichia coli è l’agente eziologico più comunemente isolato, responsabile dell’85% delle batteriurie asintomatiche e dei casi di cistiti acute non complicate. L’adesione di E.coli uropatogeni (UPEC) alle cellule uroepiteliali è determinato da specifiche interazioni tra le adesine del patogeno e i recettori della cellula ospite. Tali infezioni rappresentano anche una delle più frequenti complicanze di molte patologie neurodegenerative. Sebbene la maggiore suscettibilità dei pazienti neuropatici alle UTIs sia stata da sempre ricondotta alla discinesia vescicale conseguente a questa condizione patologica, recenti evidenze scientifiche supportano l’idea che l’alterazione morfo-fisiologica dell’urotelio secondaria a traumi midollari, caratterizzata da perdita delle cellule a ombrello e rapido differenziamento delle cellule dello strato intermedio, possa determinare la maggiore predisposizione alle UTIs. A tal riguardo, la linea di ricerca ha previsto lo studio dell’espressione di markers di differenziamento uroteliale e dei principali componenti delle placche uroteliali. Dai dati emersi appare evidente che in seguito a trauma midollare si genera una compromissione della integrità superficiale dell’urotelio, con variazione dell’espressione delle citocheratine e delle uroplachine, che renderebbero l’epitelio vescicale più vulnerabile all’attacco dei batteri. L’uroepitelio non ricopre solo la funzione di barriera di permeabilità, ma è in grado di comunicare con il sistema nervoso, di ricevere stimoli chimici e fisiologici e di rilasciare molecole segnale. Dal momento che abbiamo recentemente dimostrato un legame tra recettori metabotropici per il glutammato (mGluRs) e sistema immune, si è voluto verificare se tali recettori, già identificati in molti organi periferici, venissero espressi anche in vescica e potessero influire sui meccanismi di difesa dell’urotelio. Noi descriviamo per la prima volta la presenza degli mGluRs in vescica di topo e di uomo e, in relazione ai risultati ottenuti dall’effetto del trattamento farmacologico di tali recettori sul meccanismo di internalizzazione batterica nelle cellule uroteliali, riteniamo che i farmaci modulatori degli mGluRs possano costituire nuovi target terapeutici nel trattamento delle UTIs.
The urinary tract infections (UTIs) are among the most frequent human infections: among bacteria, Escherichia coli is the commonest isolated, responsible of 85% of asymptomatic bacteriuria and acute cystitis. The adhesion of uropathogenic E.coli (UPEC) to the uroepithelial cells is determined by specific interactions between the pathogen adhesins and host cell receptors. These infections are also one of the most frequent complicances which occur in many neurodegenerative diseases. Although the increased susceptibility of neuropathic patients to UTIs has always been attributed to the bladder dyskinesia resulting from this condition, recent scientific evidences support the idea that the morphological and physiological alterations of the urothelium subsequent to the spinal cord injury and characterized by umbrella cells loss and rapid differentiation of intermediate layer cells can determine the increased predisposition to UTIs. In this regard, our research has been focused on the study of urothelial differentiation markers and on the expression of components of the urothelial plaques. The results suggest that following a spinal cord injury the urothelium surface integrity is lost thus the subsequent alterated expression of cytokeratins and uroplakines would make the bladder epithelium more vulnerable to bacterial attack. The uroepithelium well as representing the main barrier to assure the permeability is also able to actively communicate with the nervous system either receiving chemical and physiological stimuli or releasing signal molecules. Since recentely we demonstrated a link between metabotropic glutamate receptors (mGluRs) and the immune system, we wanted to even further investigate whether these receptors, already identified in many peripheral organs, are also expressed in bladder and if they could affect the urothelium defense mechanisms. For the first time, here we describe the presence of mGluRs in the mouse and human bladder and, according to results obtained, how these receptors when modulated with selective ligands, exert effects on bacterial internalization mechanism into urothelial cells. We believe that mGluRs drugs modulators can provide new therapeutic strategies for the treatment of UTIs.

Submitted by Automa??o e Estat?stica (sst@bczm.ufrn.br) on 2018-04-02T15:20:07Z No. of bitstreams: 1 RaysaVanessaDeMedeirosFreitas_DISSERT.pdf: 1441664 bytes, checksum: 48e9822af12723aec191fe48069617d7 (MD5)
Approved for entry into archive by Arlan Eloi Leite Silva (eloihistoriador@yahoo.com.br) on 2018-04-06T11:41:38Z (GMT) No. of bitstreams: 1 RaysaVanessaDeMedeirosFreitas_DISSERT.pdf: 1441664 bytes, checksum: 48e9822af12723aec191fe48069617d7 (MD5)
Made available in DSpace on 2018-04-06T11:41:38Z (GMT). No. of bitstreams: 1 RaysaVanessaDeMedeirosFreitas_DISSERT.pdf: 1441664 bytes, checksum: 48e9822af12723aec191fe48069617d7 (MD5) Previous issue date: 2018-02-16
Introdu??o: a confian?a no equil?brio ? definida como ?a habilidade de um indiv?duo de manter o equil?brio durante a realiza??o das atividades de vida di?ria? e ? afetada pelas cren?as pessoais. Portanto, um sujeito que relata uma baixa confian?a no equil?brio pode apresentar pior desempenho do equil?brio postural. Uma das ferramentas mais utilizadas para quantificar a confian?a no equil?brio de indiv?duos da comunidade ? a escala Activities-specific Balance Confidence (ABC), tanto na vers?o original (ABC-16) quanto na vers?o curta (ABC-6). A escala ABC foi traduzida e adaptada para a popula??o de idosos brasileiros. Entretanto, o estudo de suas propriedades psicom?tricas ainda se faz necess?rio, al?m da defini??o de pontos de corte capazes de diferenciar idosos com e sem d?ficits no equil?brio postural. Objetivos: avaiar as propriedades psicom?tricas das escalas ABC-16 e ABC-6 e determinar pontos de corte capazes de diferencias idosos comunit?rios com d?ficits no equil?brio postural. M?todos: trata-se de um estudo metodol?gico que seguiu as recomenda??es do Consensus-based Standards for the Selection of Health Measurement Instruments (COSMIN) realizado de abril a novembro de 2017. O n?vel de confian?a no equil?brio foi avaliado pela ABC-16 e ABC-6. Para mensurar a confiabilidade interobservador, duas avalia??es foram realizadas por avaliadores distintos com 30 minutos de intervalo entre elas. Ap?s uma semana, um dos avaliadores reaplicou a escala para verificar a confiabilidade intraobservador. A ordem dos avaliadores foi determinada aleatoriamente. Um terceiro avaliador aferiu o equil?brio postural dos indiv?duos por meio da Escala de Equil?brio de Berg (EEB), as quatro condi??es do modified Clinical Test of Sensory Interaction and Balance (mCTSIB) e o teste de Apoio Unipodal (AU); o medo de cair por meio da Falls Efficacy Scale-International (FES-I), e a mobilidade por meio do teste de caminha de 4 metros (TC4m). O teste de correla??o de Spearman foi utilizado para determinar as validades de construto e crit?rio das escalas ABC-16 e ABC-6. A consist?ncia interna das escalas foi avaliada por meio do coeficiente ? de Cronbach, enquanto que as confiabilidades das escalas ABC-16 e ABC-6 foram mensuradas pelo Coeficiente de Correla??o Intraclasse (CII). Uma an?lise de regress?o linear foi utilizada para identificar as poss?veis vari?veis preditoras da confian?a no equil?brio e o teste de Mann-Whitney foi adotado para testar as diferen?as entre os sexos e entre os idosos com e sem queixas de tontura. Resultados: as escalas ABC-16 e ABC-6 mostraram uma correla??o estatisticamente significativa com a maioria das medidas de equil?brio postural, com a FES-I e o TC4m. A escala ABC-6 tamb?m apresentou correla??o estatisticamente significativa com o padr?o ouro para confian?a no equil?brio, a escala ABC-16 (r=0.958, p<0,001). A consist?ncia interna pelo ? de Cronbach da ABC-16 e da ABC-6 foi de 0.943 e 0.901, respectivamente. Para a ABC-6, observou-se confiabilidades intra e interexaminador de ICC=0.956 e ICC=0.946, respectivamente. J? para a escala ABC-16, encontramos confiabilidades intra e interexaminador de 0.972 e 0.968, respectivamente. A curva Receiver Operating Characteristics (ROC) indicou um valor de ?67% como o melhor ponto de corte para identificar idosos com d?ficits no equil?brio na escala ABC-16 (sensibilidade: 81%; especificidade: 77.4%), e ?44% (sensibilidade: 87.5%; especificidade: 82.1%) na escala ABC-6. Conclus?o: tanto a escala ABC-16 quanto a ABC-6 apresentam, no geral, uma boa validade, e excelentes confiabilidades intra e interobservador e consist?ncia interna. Portanto, estas escalas s?o adequadas para a avalia??o da confian?a no equil?brio de idosos brasileiros residentes na comunidade. Al?m disso, os pontos de corte para as escalas encontrados podem ser ?teis no rastreio de idosos residentes na comunidade com d?ficits no equil?brio postural e maior risco de cair.
Introduction: Balance confidence is described as ?a person?s ability to maintain balance while performing activities of daily living? and is affected by an individual?s beliefs. Therefore, an individual who report a low confidence in balance may present lower postural balance performances. One of the most used tools to quantify the balance confidence of the community-dwelling individual is the Activities-specific Balance Confidence (ABC) scale, in its original (ABC-16) and short (ABC-6) versions. The ABC scale was translated and adapted to the Brazilian older adults. However, the study of the psychometric properties is still required and also cut-off points for both scales have not been provided yet. Objectives: To investigate the psychometric properties of the ABC-16 and ABC-6, and to determine cut-off points capable to identity community-dwelling older adults with deficits in postural balance and higher risk of falling. Methods: This is a psychometric study that followed the Consensus-based Standards for the Selection of Health Measurement Instruments (COSMIN). This study took place from April 2017 to November 2017. The level of balance confidence was assessed by the ABC-16 and ABC-6. To assess the interrater reliability, two evaluations with a 30-minute interval was performed by distinct evaluators. After one week, one of the evaluators re-applied the ABC-16 to verify the intrarater reliability. The order of the evaluators was chosen randomly. A third examiner assessed the postural balance of the individuals through the Berg Balance Scale (BBS), the modified Clinical Test of Sensory Interaction on Balance (mCTSIB) and the Unilateral Stance (US), the fear of falling through the Falls Efficacy Scale-International (FES-I), and mobility through the 4-m walk test (4MWT). Results: The ABC-16 and ABC-6 showed a statistically significant correlation with most of the measures of postural balance, FES-I and 4MWT. The ABC-6 also presented statistically significant correlation with the gold standard, the ABC-16 (r=0.958, p<0,001). The internal consistency analysis of the ABC-16 and ABC-6 yielded a Cronbach?s ? value 0.943 and 0.901, respectively. Both ABC-16 and ABC-6 presented excellent intra and interrater reliability. The Receiver Operating Characteristics (ROC) curve indicated a value of ?67% as the best cut-off point to identify older adults with balance impairments in the ABC-16 (sensitivity: 81%; specificity: 77.4%), and ?44% (sensitivity: 87.5%; specificity: 82.1%) in the ABC-6. Conclusion: Both ABC-16 and ABC-6 have an overall good validity, and excellent internal consistency, and intra and inter-rater reliability. Therefore, these scales are suitable tools for assessing balance confidence in the Brazilian community-dwelling elderly people.

El desenvolupament de noves teràpies s’està duent a terme arreu del món per poder fer front a les necessitats clíniques que actualment no disposen de tractament. En particular, els avenços en productes medicinals de teràpia avançada (ATMP) són una gran promesa per al tractament de malalties sense altres opcions terapèutiques. Tanmateix, els investigadors i les autoritats reguladores que implementen aquestes teràpies lluiten per estandarditzar tant els protocols com els productes finals. Entre els reptes s’inclouen l’elevada intervariabilitat de donants i mecanismes d’acció complexos. A més, és necessari demostrar l’activitat biològica d’aquestes teràpies mitjançant assajos de potència. Aquesta tesi consisteix en el desenvolupament i caracterització de dos ATMP basats en cèl·lules multipotents estromals mesenquimals (MSC) i cèl·lules T específiques de virus (VST). D'una banda, s’ha fet l’avaluació d'un test de potència i identitat per la producció de MSC aïllades de la gelatina de Wharton (WJ) i de la medul·la òssia (BM). L’objectiu proposat per MSC era realitzar: a) un assaig de potència per avaluar la capacitat immunomoduladora de les MSC; b) la revisió de l’expressió del HLA-DR pels criteris de definició de les MSC; i c) l'aplicació d’una eina per gestionar el risc. En aquest treball es presenta l’optimització d’un assaig d’immunopotència, validat i aprovat per l’autoritat competent per a l’alliberament de producte. S’ha estudiat l’expressió del HLA-DR, marcador suposadament negatiu, en les BM-MSC de grau clínic. Els resultats van mostrar una correlació entre l’expressió del HLA-DR i els nivells d’IL-17F i IL-33. L'expressió del HLA-DR no va afectar la identitat de les MSC, ni el potencial de diferenciació ni la capacitat immunomoduladora. Per reforçar aquests resultats, es van realitzar estudis interlaboratori obtenint resultats similars. L'ús de suplements basats en sèrum humà o lisat plaquetari no mostrava diferències en l'expressió de HLA-DR en MSC. També es va implementar la gestió de riscos com a eina de qualitat per detectar debilitats d’un bioprocés. Aquests enfocaments s’han dut a terme per MSC en assajos clínics. D'altra banda, es va realitzar el desenvolupament d'un protocol d'expansió ex vivo de VST. La teràpia amb VST està destinada a pacients immunocompromesos, susceptibles de patir una reactivació o infecció de novo de l’herpesvirus entre d’altres. És el cas del citomegalovirus (CMV), que pot produir una infecció lleu en individus sans, però té una elevada morbiditat i mortalitat en individus immunocompromesos. Els medicaments antivirals disponibles poden produir toxicitat i no sempre són efectius. La immunoteràpia adoptiva ofereix una alternativa als pacients en una situació crítica i sense altres opcions terapèutiques. Per satisfer aquesta demanda es va elaborar un protocol de fabricació de VST fàcilment transferible als estàndards farmacèutics. Amb el mètode proposat, després d’un cocultiu de 14 dies amb cèl·lules dendrítiques polsades amb pp65, es van obtenir un gran nombre de VST. El cultiu es basava en la tecnologia G-Rex i es suplementava amb IL-2, IL-7, IL-15, i anticossos anti-CD3 i anti-CD28. El producte final es va caracteritzar àmpliament i estava format per limfòcits T CD4+ i CD8+, on la subpoblació majoritària corresponia a les cèl·lules T efectores de memòria, població coneguda per proporcionar una funció efectora. Cal destacar la citotoxicitat de les cèl·lules expandides específicament enfront al pp65. Els estudis d’al·loreactivitat amb HLA totalment incompatibles, van mostrar una lisi cel·lular per sota del 5%. En resum, s’ha descrit un protocol transferible a les normes de correcta fabricació actuals i un producte segur i eficaç in vitro, funcional després de la descongelació. El darrer fet, facilitaria la generació d’un banc al·logènic de VST. Les perspectives de futur inclourien la fabricació de cèl·lules T específiques per a múltiples virus.
Innovative therapies are being developed worldwide to tackle unmet clinical needs. In particular, progress in advanced therapy medicinal products (ATMP) has shown great promise for the treatment of diseases with no other option available. However, researchers and regulatory authorities deal with the sophisticated nature of these medicines, and struggle to standardise both production protocols and final product formulation. Challenges related to the living nature of these products include high donor intervariability and complex mechanisms of action, which are sometimes not completely understood. Additionally, these newly therapies need to demonstrate biological activity with potency assays. This dissertation comprises the development and characterisation of two different ATMP based on multipotent mesenchymal stromal cells (MSC) and virus-specific T cells (VST). On the one hand, assessment of identity and potency for product release of MSC isolated from Wharton’s jelly (WJ) and bone marrow (BM) in the context of current good manufacturing practice (cGMP) production is performed. In this regard, we aimed at proposing: a) a potency assay for assessing immunomodulation capacity of MSC; b) the revision of HLA-DR expression profile for MSC definition criteria; and c) the application of risk management methodologies in the assessment of product quality. The optimisation of an immunopotency assay, validated, and approved by the competent authority for product release is presented. Moreover, other quality attributes of MSC are addressed. Regarding BM-MSC, the apparently random expression of HLA-DR, a marker that was expected negative in expansion cultures of MSC, is studied in clinical grade productions. Our findings showed correlation of HLA-DR expression with levels of IL-17F and IL-33. Expression of HLA-DR did not affect MSC identity, differentiation potential nor immunomodulatory capacity. To further strengthen these outcomes, interlaboratory studies were performed obtaining similar results. Furthermore, the use of either human sera or platelet lysate supplements showed no differences in terms of HLA-DR expression. A risk management assessment methodology was also implemented as a tool for quality by design to detect weaknesses of an established bioprocess involving MSC products already in clinical trials. On the other hand, regarding T lymphocytes, the development of a protocol for ex vivo expansion of VST was performed. VST therapy is intended for immunocompromised patients, which are susceptible of reactivation or de novo infection of herpesviruses among others. This is the case of cytomegalovirus (CMV) that undergoes a mild infection in healthy individuals but has been associated to a high morbidity and mortality in immunocompromised individuals. Unfortunately, available antiviral drugs can produce toxic side effects and are not always effective. Adoptive immunotherapy offers an alternative approach for those patients in a critical situation with no other therapeutic option. Therefore, we developed a protocol for VST scale-up manufacture easily transferable to pharmaceutical standards. Following with the method proposed, we obtained large number of CMV pp65-specific T cells after 14-day co-culture with pp65 pulsed dendritic cells. Culture was based on G-Rex bioreactor technology and supplemented with IL-2, IL-7, IL-15, anti-CD3 and anti-CD28 antibodies. The final product was extensively characterised in terms of identity, purity and potency. VST product was comprised of both CD4+ and CD8+ T lymphocytes, and effector memory T cells represented the major subset, which are known to provide effector function. Most importantly, we successfully demonstrated pp65 specific cytotoxicity of the expanded cells. Interestingly, complete HLA mismatch alloreactivity resulted in less than 5% cell lysis. In summary, a feasible protocol transferable to cGMP was described for an in vitro safe and effective product, which remain functional after thawing, thus providing practical evidence for the generation of an allogeneic third-party bank. Future perspectives would include the manufacture of multivirus-specific T cells.

La terapia CAR-T rappresenta un approccio promettente, ma ha riportato una ridotta efficacia nella leucemia mieloide acuta (AML), a causa dell’eterogeneità del tumore, dell’assenza di antigeni target AML-specifici e del ruolo del microambiente leucemico nella protezione dei blasti e delle cellule staminali leucemiche (LSC). La nicchia midollare, nella quale risiedono le LSC, è coinvolta in attività che promuovono la progressione leucemica e sopprimono l’ematopoiesi sana. Quindi ipotizziamo che bersagliare le LSC nascoste nella nicchia potesse migliorare l’efficacia delle CAR-T. Per testare la nostra ipotesi, abbiamo agito su due fronti: 1) promuovere una migrazione efficiente delle CAR-T nella nicchia midollare, 2) selezionare un antigene target ristretto ai blasti leucemici e alle LSC. Prima, abbiamo proposto una strategia per guidare le cellule CD33.CAR CIK (Cytokine-Induced Killer), una sottopopolazione di cellule T effettrici, verso la nicchia leucemica. La chemochina CXCL12, rilasciata dalle cellule mesenchimali stromali (MSC), nella nicchia midollare, e il suo recettore CXCR4, sono coinvolti nella regolazione della migrazione dei leucociti all’interno della nicchia. Quindi, abbiamo ipotizzato che sfruttare questo asse potesse migliorare la capacità di homing delle CD33.CAR-CIK nella nicchia e favorire l’eradicazione della leucemia. Tuttavia i protocolli di manipolazione ex vivo delle CD33.CAR-CIK riducono l’espressione di CXCR4, compromettendo la capacità delle cellule infuse di raggiungere la nicchia. Quindi per implementare la capacità di homing delle CD33.CAR-CIK nel microambiente midollare, abbiamo sviluppato delle CD33.CAR-CIK overesprimenti CXCR4, nella sua forma wild-type o iperattiva mutata. Le CIK ingegnerizzate con i costrutti CD33.CAR-CXCR4 hanno mostrato un consistente aumento dell’espressione di CXCR4, senza riportare alterazioni fenotipiche e nelle funzioni effettrici CAR-associate. Inoltre, rispetto alle CD33.CAR-CIK, le cellule CD33.CAR-CXCR4WT -CIK ed in particolare le CD33.CAR-CXCR4MUT-CIK hanno dimostrato non solo una superiore risposta chemotattica in vitro verso il CXCL12 ed i surnatanti delle MSC, ma anche un aumentato homing in vivo. In seguito, per promuovere lo sviluppo di un approccio CAR-T più efficace e sicuro, abbiamo proposto di re-indirizzare il CAR verso un antigene espresso selettivamente dalle cellule AML, ma assente sulle cellule staminali ematopoietiche (HSC). TIM-3 è un immune checkpoint, svolge un ruolo centrale nella regolazione delle risposte immunitarie nell’AML e costituisce un marcatore selettivo per le LSC, senza essere espresso dalle HSC. Abbiamo disegnato un CAR di terza generazione diretto contro TIM-3, utilizzando la porzione scFv derivante da un anticorpo monoclonale anti-TIM-3. In vitro, le TIM-3.CAR-CIK hanno dimostrato di eliminare sia le linee AML che i blasti primari, senza dare tossicità verso le cellule TIM-3+ sane, come le CIK attivate, i monociti e le cellule NK. Inoltre, le TIM-3.CAR-CIK hanno eliminato in maniera selettiva le LSC (CD34+ CD38-). Infine, le TIM-3.CAR-CIK hanno mantenuto le loro capacità effettrici nonostante multiple ristimolazioni in vitro, gettando le basi per lo studio di questo costrutto in vivo. Complessivamente, entrambi gli approcci, uno implementando l’homing delle CAR-CIK alla nicchia midollare e l’altro conferendo una superiore selettività, potrebbero migliorare l’efficacia della terapia CAR-T nel contesto dell’AML.
Chimeric Antigen Receptor (CAR) T-cell therapy has produced remarkable clinical responses in patients affected by acute lymphoblastic leukemia. Unfortunately, CAR T-cells have not been equally successful in acute myeloid leukemia (AML) due to tumor heterogeneity, lack of truly AML-restricted target antigens and the role of leukemia microenvironment in blasts protection and leukemia stem cells (LSCs) maintenance. Specifically, the bone marrow (BM) niche, where LSCs reside, is involved in leukemia promoting activities whilst suppressing normal hematopoiesis. Therefore, we hypothesized that targeting LSCs at their location may enhance the potency and selectivity of CAR-T cells. To address this issue, we have designed two aims: 1) promote rapid and efficient localization of CAR T-cells within the BM niche, 2) select a leukemia-restricted antigen to specifically target AML blasts and LSCs. First, we proposed to harness CD33.CAR-redirected Cytokine-Induced Killer (CIK) cells, an alternative effector T-cell population with acquired NK-like cytotoxic activity as well as minimal alloreactivity, to selectively route their activity to leukemia transformed niche. The chemokine ligand 12 (CXCL12), released by mesenchymal stromal cells (MSCs) within the medullary niche, and its chemokine receptor 4 (CXCR4) are two pivotal players regulating leukocytes trafficking to the BM. In AML, CXCL12 interacts with CXCR4 overexpressed on blasts, promoting their migration and homing in the niche. Hence, taking advantage of this axis might facilitate CD33.CAR-CIK cells homing to the BM and therefore leukemia eradication. However, ex vivo manipulation protocols of CD33.CAR-CIK cells consistently downregulate CXCR4 expression and may affect the capacity of adoptively infused cells to migrate to BM and exert their anti-leukemic action. Therefore, to improve CD33.CAR-CIKs homing in the BM microenvironment we have developed CD33.CAR-CIK cells overexpressing CXCR4, in its wild-type or hyperactive mutant form. Notably, CIK cells engineering with CD33.CAR-CXCR4 constructs led to a consistent increase in CXCR4 expression, without altering CIK cells phenotype and CAR-related effector functions. Interestingly, compared to conventional CD33.CAR-CIK cells, CD33.CAR-CXCR4WT and especially CD33.CAR-CXCR4MUT-CIK cells demonstrated significantly superior in vitro chemotactic response toward CXCL12 and MSC-derived supernatants, and greater in vivo BM homing ability and persistence. Furthermore, to develop an effective anti-AML CAR T-cell therapy, it is fundamental to identify a LSC-specific marker, sparing the normal counterpart of hematopoietic stem cells (HSCs). T-cell immunoglobulin and mucin protein 3 (TIM-3) is an immune checkpoint molecule, it plays a central role in immune responses in AML and it is an LSC-specific marker, lacking expression on HSCs. Therefore, we designed a third-generation anti-TIM-3.CAR using the single-chain fragment variable (scFv) derived from an antagonistic ligand-blocking anti-TIM-3 antibody. In vitro, TIM-3.CAR-CIK cells efficiently killed both AML cell lines and primary AML blasts, but not normal TIM-3+ activated CIK cells, monocytes and NK-cells. Notably, we observed selective elimination of primary LSC-enriched population (CD34+ CD38-). Furthermore, TIM-3.CAR-CIK cells maintained their effector functions despite multiple in vitro restimulations, setting the basis for further exploration in in vivo models. Overall, both approaches, one improving CAR-CIK cells homing to the transformed niche and the other conferring superior safety and selectivity, might improve the efficacy of anti-AML CAR-CIK therapy.

O objetivo deste estudo foi comparar o desempenho psicolingüístico de crianças com Distúrbio Específico de Linguagem (DEL) com o de crianças que apresentam desenvolvimento típico de linguagem (DTL), apontando os marcadores psicolingüísticos mais significativos do distúrbio e também comparar a eficácia de dois métodos de intervenção - Modelo de Intervenção no Meio e Modelo Neuropsicolingüístico - no desempenho psicolingüístico das crianças com DEL. Participaram desta investigação 12 pré-escolares de ambos os gêneros, com idade entre 4:0 - 6:11 anos, sendo metade deles pertencentes ao grupo experimental - crianças com DEL, submetidos à intervenção - e os demais ao grupo controle - crianças com DTL, não submetidos à intervenção. A quantificação do rendimento dos sujeitos nas distintas dimensões psicolingüísticas foi obtida mediante a utilização de diversos instrumentos, com o propósito de avaliar o nível primário, secundário e terciário da recepção e produção lingüística. Posteriormente às avaliações préintervenção, o grupo experimental foi distribuído aleatoriamente em dois grupos e submetido a dois diferentes modelos terapêuticos (primeiro ciclo), com duração de quatro meses. Ao fim deste ciclo foi reavaliado, submetido a quatro meses de terapia em que os Modelos foram alternados e os grupos novamente reavaliados. A análise estatística revelou a existência de diferença estatisticamente significante entre o desempenho do grupo experimental e controle em vários níveis de análise e produção lingüística, sendo os marcadores mais significativos encontrados os que envolvem a discriminação auditiva, análise fonológica, recepção e organização morfossintática, memória de curto prazo e habilidades pragmáticas quanto ao uso de turnos expansivos. Já a comparação da eficácia dos dois Modelos de intervenção propostos revelou que as distintas habilidades psicolingüísticas responderam de forma diferente aos mesmos, sugerindo que a combinação das estratégias dos Modelos investigados possa ser o melhor caminho quando se deseja intervir nos quadros de crianças cujas dificuldades encontram-se situadas nos níveis de análise e produção lingüística investigados neste trabalho.
This study aimed to compare the psycholinguistic performance of children with Specific Language Impairment (SLI) to children with Typical Language Development (TLD), pointing out the most significant psycholinguistic markers, and to compare the effectiveness of two intervention methods, Milieu Teaching Approach and Neuropsycholinguistic Model, in the psycholinguistic performance of children with SLI. The subjects were 12 pre-school boys and girls, 4:00 to 6:11 years old; half of them took part in the experimental group - children with SLI submitted to intervention - and the others in the control group - children with TLD not submitted to intervention. The subject performance quantification in distinct psycholinguistic dimensions was obtained through several tools in order to evaluate the primary, secondary and tertiary levels of linguistic reception and production. After pre-intervention evaluations, the experimental group was randomly distributed into two study groups and submitted to two different therapeutic models (first cycle) during four months. At the end of this cycle, it was evaluated again, submitted to four-month therapy with alternating Models and re-evaluated. Statistical analysis showed the existence of statistically significant difference in the performance between the experimental group and the control one in several levels of linguistic analysis and production. The most significant markers involve auditory discrimination, phonological analysis, morphosyntactic reception and production, short-term memory and pragmatic abilities in relation to the use of expansive turns. The comparison of the effectiveness between the two proposed Models showed that distinct psycholinguistic abilities responded differently to themselves, which suggests that the combination of strategies of the studied Models be the best way to intervene in the performance of children whose difficulties lie in the investigated analysis and linguistic production levels of this study.

Alexander Roßnagel celebrated his 70th birthday on September 13, 2020. The jubilee has shaped innovative research approaches in many areas of environmental and technology law. His interdisciplinary studies often include methodological advancements and combine specific design problems with important questions of fundamental rights and social cooperation – always aiming at responsible decisions for a socially acceptable future. The articles of the festschrift concern many facets of his work and bring together legal and interdisciplinary perspectives on essential challenges regarding the design of legal norms and innovative technologies, privacy and data protection, the conception and regulation of digitization, environmental regulation and organizational development. With contributions by Christiane Borchard, Benedikt Buchner, Alfred Büllesbach, Ernestine Dickhaut, Alexander Dix, Peter Dräxler, Christoph Ewen, Lothar Fischer, Martin Führ, Shizuo Fujiwara, Kurt Geihs, Christian Ludwig Geminn, Rüdiger Grimm, Volker Hammer, Anja Hentschel, Eric Hilgendorf, Michel-A. Horelt, Gerrit Hornung, Silke Jandt, Andreas Janson, Paul C. Johannes, Dieter Klumpp, Nicole Krämer, Michael Kreutzer, Herbert Kubicek, Robert Kuhn, Christel Kumbruck, Jörn Lamla, Philip Laue, Jan Marco Leimeister, Natalie Maier, Fabiano Menke, Hans-Jürgen Müggenborg, Günter Müller, Bernhard Nagel, Maxi Nebel, Uwe Neuser, Tadashi Otsuka, Ulrich Pordesch, Niklas Radenbach, Philipp Richter, Gerhard Roller, Peter Rott, Christoph Schnabel, Roland Steidle, Martin Steinebach, Gerd Stumme, Ali Sunyaev, Mayu Terada, Wolfgang Thaenert, Michael Waidner, Thilo Weichert, Tsuneharu Yonemaru

For children with intellectual disabilities it is easier to remember content in relation to movement, a specific situation important to them, as a result of multisensory contact with stimuli accompanied by the emotional content. Verbotonal method ensures that as all the exercises there are performed together with motor activation allowing for sensory stimulation: vestibular, proprioceptive both kinetic and tactile, whose proper functioning sets the base for perception development in the area of superior sensory systems, i.e., auditory and visual. Exercises used in the method mobilize children for action, stimulate cognitive and motor activity, perfect their attention focus, help them with visual perception, following objects with their eyes, or keeping focus on an object. They also stimulate imagination and creative expression, develop general and musical hearing, improve gross motor coordination as well as precise movements, precision, velocity, range, purposefulness and esthetics of their movements; they perfect self and space orientation, help with self‑esteem and self‑acceptance, mould their identity and body awareness, help level tactile oversensitivity/undersensitivity. Phonatory games can make it easier for children to produce sound, improve their articulation and phonation and musical elements better respiratory functions. Through joint games with other children or with the therapist, this method also facilitates establishing contact with another human being.

Melanom je globalni zdravstveni problem s kontinuiranim porastom u incidence. Rezultati tretmana metastatskog melanoma su, do skorašnjih napredovanja u terapijama, bili slabi, s medijanom ukupnog preživljavanja (OS) od 7,5 mjeseci i petogodišnjom stopom preživljavanja 6%. U kliničkim istraživanjima za metastatski melanom, selektivni inhibitori BRAF gena, vemurafenib i dabrafenib, pokazali su značajnu antitumorsku aktivnost i poboljšanje u OS i PFS kada se porede s dakarbazinom. Međutim, skoro će svaki pacijent tretiran BRAF inhibitorima imati progresiju bolesti, a tumori pokazuju reaktivacije MAPK puta u vrijeme pojave rezistencije. Specifična BRAF inhibicija vodi ka paradoksalnoj aktivaciji ćelija s RAS divljim “wild” genom uzvodno u MAPK putu i iz tih razloga vodi rezistenciji na terapiju, ćelijskoj proliferaciji i povećanoj stopi RAS kožnog toksiciteta. Pretklinički podaci sugerisali su da inhibitori MEK gena u MAPK putu mogu da zaustave rast i isprovociraju ćelijsku smrt kod nekih BRAF pozitivnih melanomskih tumora. Selektivni inhibitori MEK1 i MEK2 su cobimetinib i trametinib. Kombinovanjem BRAF+MEK inhibicije postiže se produženje terapijskog odgovora, odgađanje rezistencija i smanjuje pojava novih kutanih SCC/KA udruženih s BRAF inhibicijom. Kombinacija dabrafenib+ trametinib i vemurafenib+cobimetinib odobrena je za pacijente s neresktabilnim ili metastatskim melanomom s tumorima koji imaju mutaciju na BRAF genu. Klinička vrijednost intermitentne terapije za sada nije definisana. Podaci iz kliničkih istraživanja sugerišu da selekcionirani pacijenti mogu imati benefit od terapije uprkos razvijanju novih metastaza. Uvođenje ovih terapija u adjuvantno područje može dodatno poboljšati ishod i liječenje ove bolesti.

Abstract Human’s motion and its mechanisms had become interesting in the last years, where the medecine’s field search for rehabilitation methods for handicapped persons. Other fields, like sport sciences, professional or military world, search to distinguish profiles and ways to train them with specific purposes. Besides, recent findings in neuroscience try to describe these mechanisms from an organic point of view. Until now, different researchs had given a model about control motor that describes how the union between the senses’s information allows adaptable movements. One of this sense is the proprioception, the sense which has a quite big factor in the orientation and position of the body, its members and joints. For this reason, research for new strategies to explore proprioception and improve the theories of human motion could be done by three different vias. At first, the sense is analysed in a case-study where three groups of persons are compared in a controlled enviroment with three experimental tasks. The subjects belong to each group by the kind of sport they do: sedentary, normal sportsmen (e.g. athletics, swimming) and martial sportmen (e.g. karate, judo). They are compared thinking about the following hypothesis: “Martial Sportmen have a better proprioception than of the other groups’s subjects: It could be due to the type of exercises they do in their sports as empirically, a contact sportsman shows significantly superior motor skills to the members of the other two groups. The second via are records from encephalogram (EEG) while the experimental tasks are doing. These records are analised a posteriori with a set of processing algorithms to extract characteristics about brain’s activity of the proprioception and motion control. Finally , the study tries to integrate graphic tools to make easy to understand final scientific results which allow us to explore the brain activity of the subjects through easy interfaces (e.g. space-time events, activity intensity, connectivity, specific neural netwoks or anormal activity). In the future, this application could be a complement to assist doctors, researchers, sports center specialists and anyone who must improve the health and movements of handicapped persons. Keywords: proprioception, EEG, assesment, rehabilitation.References: Röijezon, U., Clark, N.C., Treleaven, J. (2015). Proprioception in musculoskeletal rehabilitation. Part 1: Basic science and principles of assessment and clinical interventions. ManualTher.10.1016/j.math.2015.01.008. Röijezon, U., Clark, N.C., Treleaven, J. (2015). Proprioception in musculoskeletal rehabilitation. Part 2: Clinical assessment and intervention. Manual Ther.10.1016/j.math.2015.01.009. Roren, A., Mayoux-Benhamou, M.A., Fayad, F., Poiraudeau, S., Lantz, D., Revel, M. (2008). Comparison of visual and ultrasound based techniques to measure head repositioning in healthy and neck-pain subjects. Manual Ther. 10.1016/j.math.2008.03.002. Hillier, S., Immink, M., Thewlis, D. (2015). Assessing Proprioception: A Systematic Review of Possibilities. Neurorehab. Neural Repair. 29(10) 933–949. Hooper, T.L., James, C.R., Brismée, J.M., Rogers, T.J., Gilbert, K.K., Browne, K.L, Sizer, P.S. (2016). Dynamic Balance as Measured by the Y-Balance Test Is Reduced in Individuals with low Back Pain: A Cross-Sectional Comparative Study. Phys. Ther. Sport,10.1016/j.ptsp.2016.04.006. Zemková, G., Stefániková, G., Muyor, J.M. (2016). Load release balance test under unstable conditions effectivelydiscriminates between physically active and sedentary young adults. Glave, A.P., Didier, J.J., Weatherwax, J., Browning, S.J., Fiaud, Vanessa. (2014). Testing Postural Stability: Are the Star Excursion Balance Test and Biodex Balance System Limits of Stability Tests Consistent? Gait Posture. 43(2016) 225-227. Han, Jian., Waddington, G., Adams, R., Anson, J., Liu, Y. (2014). Assessing proprioception: A critical review of methods. J. Sport Health Sci.10.1016/j.jshs.2014.10.004. Hosp, S., Bottoni, G., Heinrich, D., Kofler, P., Hasler, M., Nachbauer, W. (2014). A pilot study of the effect of Kinesiology tape on knee proprioception after physical activity in healthy women. J. Sci. Med. Sport. 18 (2015) 709-713. Mima, T., Terada, K., Ikeda, A., Fukuyama, H., Takigawa, T., Kimura, J., Shibasaki, H. (1996). Afferent mechanism of cortical myoclonus studied by proprioception-related SEPs. Clin. Neurophysiol. 104 (1997) 51-59. Myers, J.B., Lephart, S.M. (2000). The Role of the Sensorimotor System in the Athletic Shoulder. J. Athl.Training.35 (3) 351-363. Rossi, S., della Volpe, R., Ginannesch, F., Ulivelli, M., Bartalini, S., Spidalieri, R., Rossi, A. (2003). Early somatosensory processing during tonic muscle pain in humans: relation to loss of proprioception and motor 'defensive' strategies. Clin. Neurophysiol. 10.1016/S1388-2457(03)00073-7. Chaudhary, U., Birbaumer, N., Curado, M.R. (2014). Brain-Machine Interface (BMI) in paralysis. Ann. Phys. Rehabil. Med.10.1016/j.rehab.2014.11.002. Delorme, A., Makeig, S. (2003). EEGLAB: an open source toolbox for analysis of single-trial EEG dynamics including independent component analysis. J. Neurosci. Meth.10.1016/j.jneumeth.2003.10.009. Morup, M., Hansen, L.K., Arnfred, S.M. (2006). ERPWAVELAB: A toolbox for multi-channel analysis of time-frequency transformed event related potentials. J. Neurosci. Meth.10.1016/j.jneumeth.2003.11.008. Kaminski, M., Blinowska, K., Szelenberger, W. (1996). Topographic analysis of coherence and propagation of EEG activity during sleep and wakefulness. Clin. Neurophysiol. 102 (1997) 216-227. Korzeniewska, A., Manczak, M., Kaminski, M., Blinowska, K.J., Kasicki, S. (2003). Determination of information flow direction among brain structures by a modified directed transfer function (dDTF) method. J. Neurosci. Meth.10.1016/S0165-0270(03)00052-9. Morup, M., Hansen, L.K., Parnas, J., Arnfred, S.M. (2005). Parallel Factor Analysis as an exploratory tool for wavelet transformed event-related EEG. Neuroimage. 10.1016/j.neuroimage.2005.08.005. Barwick, F., Arnett, P., Slobounov, S. (2011). EEG correlates of fatigue during administration of a neuropsychological test battery. Clin. Neurophysiol. 10.1016/j.clinph.2011.06.027. Osuagwu, B.A., Vuckovic, A. (2014). Similarities between explicit and implicit motor imagery in mental rotation of hands: An EEG study. Neuropsycholgia. Buzsáki, G. (2006). Rhythms of the brain. Ed. Oxford. USA. Trappenberg, T.P. (2010). Fundamentals of Computational Neuroscience. Ed. Oxford. UK. Koessler, L., Maillard, L., Benhadid, A., Vignal, J.P., Felblinger, J., Vespignani, H., Braun, M. (2009). Automated cortical projection of EEG: Anatomical correlation via the international 10-10 system. Neuroimage. 10.1016/j.neuroimage.2009.02.006. Jurcak, V., Tsuzuki, Daisuke., Dan, I. (2007). 10/20, 10/10, and 10/5 systems revisited: Their validity as relativehead-surface-based positioning systems. Neuroimage. 10.1016/j.neuroimage.2006.09.024. Chuang, L.Y., Huang, C.J., Hung, T.M. (2013). The differences in frontal midline theta power between successful and unsuccessful basketball free throws of elite basketball players. Int. J. Psychophysiology.10.1016/j.ijpsycho.2013.10.002. Wang, C.H., Tsai, C.L., Tu, K.C., Muggleton, N.G., Juan, C.H., Liang, W.K. (2014). Modulation of brain oscillations during fundamental visuo-spatialprocessing: A comparison between female collegiate badmintonplayers and sedentary controls. Psychol. Sport Exerc. 10.1016/j.psychsport.2014.10.003. Proverbio, A.L., Crotti, N., Manfredi, Mirella., Adomi, R., Zani, A. (2012). Who needs a referee? How incorrect basketball actions are automatically detected by basketball players’ brain. Sci Rep-UK. 10.1038/srep00883. Cheng, M.Y., Hung, C.L., Huang, C.J., Chang, Y.K., Lo, L.C., Shen, C., Hung, T.M. (2015). Expert-novice differences in SMR activity during dart throwing. Biol. Psychol.10.1016/j.biopsycho.2015.08.003. Ring, C., Cooke, A., Kavussanu, M., McIntyre, D., Masters, R. (2014). Investigating the efficacy of neurofeedback training for expeditingexpertise and excellence in sport. Psychol. SportExerc. 10.1016/j.psychsport.2014.08.005. Park, J.L., Fairweather, M.M., Donaldson, D.I. (2015). Making the case for mobile cognition: EEG and sports performance. Neurosci. Biobehav. R. 10.1016/j.neubiorev.2015.02.014. Babiloni, C., Marzano, N., Infarinato, F., Iacoboni, M., Rizza, G. (2009). Neural efficency of experts’ brain during judgement of actions: A high -resolution EEG study in elite and amateur karate athletes. Behav. Brain. Res. 10.1016/j.bbr.2009.10.034. Jain, S., Gourab, K., Schindler-Ivens, S., Schmit, B.D. (2012). EEG during peddling: Evidence for cortical control of locomotor tasks. Clin. Neurophysiol.10.1016/j.clinph.2012.08.021. Behmer Jr., L.P., Fournier, L.R. (2013). Working memory modulates neural efficiency over motor components during a novel action planning task: An EEG study. Behav. Brain. Res. 10.1016/j.bbr.2013.11.031.